Decreased Survival After Combining Thoracic Irradiation and an Anti-PD-1 Antibody Correlated With Increased T-cell Infiltration Into Cardiac and Lung Tissues

Abstract

Purpose Lung cancer is the leading cause of cancer-related mortality in the United States. Radiation, a common component of treatment, can cause acute damage to critical organs including the lungs and the heart, but the serious toxicities from radiotherapy alone is relatively rare. A recent addition to the treatment regimen is immunotherapy, such as anti-PD-1 antibody, which blocks the inhibition of activated T cells. Combining anti-PD-1 treatment and thoracic radiation has potential for improving the outcomes of locally advanced lung cancer over traditional chemoradiation regimens, but the effect of combining these therapies on non-malignant lung tissue has not yet been investigated in preclinical models. Materials and Methods 6–8 week old C57Bl/6 mice were treated with either anti-PD-1 antibody or control IgG with or without thoracic radiation (20Gy), and survival was monitored as an end point to determine any potential increase of toxicity from the combination therapy. Immune cell infiltration into the irradiated cardiac and lung tissues was analyzed via flow cytometry and histologically. Results At 21 days post-radiation, 70% of animals in the IgG + radiation group survived, significantly more than the anti-PD-1 + radiation group (36%; p=0.0169). T cell counts were significantly elevated in both cardiac and pulmonary tissues after combination therapy as compared to anti-PD-1 antibody alone (heart: 6.1 vs 22.4, p<0.001; lung 3.4 vs 20.8, p<0.001) or control IgG plus radiation (heart 11.3 vs 22.4, p<0.05; lung 12.2 vs 20.8, p<0.05) in flow cytometric studies. Histologic analysis confirmed this increase in the comparison of anti-PD-1 antibody alone versus antibody plus irradiation (heart: 464 vs 679 cells per field, p<0.001; lung: 780 vs 1109, p<0.001) and control IgG plus radiation or combination therapy (heart: 526 vs 679 cells per field, p<0.001; lung: 848 vs 1109, p<0.05). Conclusions Combining anti-PD-1 antibody and thoracic irradiation results in T cell infiltration into lung and heart tissue and increases mortality in a preclinical model. We conclude that healthy tissue damaged by irradiation is more susceptible to further damage by activated T cells.

Safety of combined PD‐1 pathway inhibition and radiation therapy for non‐small‐cell lung cancer: A multicentric retrospective study from the GFPC

“…This kind of secondary effect could be related to a T-cell infiltration of the esophagus according to the hypothesis proposed by Myers and Du, after having exposed murine preclinical model to the therapeutic combination. 28,29 In their studies, T-cell counts were significantly elevated in both cardiac and pulmonary tissues after combination therapy as compared to treatment with radiation alone, indicating that, while prolonging the action of immune cells may enhance their antitumor activity, nonmalignant tissue damaged by irradiation is susceptible to accumulation of and further damage by activated T cells. It could be one of the limits of this treatment combination in clinical practice.…”

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

“…Increased mortality and cardiac dysfunction (illustrated by reduced ejection fraction) were observed in mice receiving cardiac RT with PD-1 blockade versus mice that only received RT [185]. Myers and Lu treated C57BL/6 mice with whole thorax irradiation in combination with an anti-PD-1 antibody and also observed reduced survival and increased numbers of T-cells in lung and heart compared to radiation alone [186]. These studies have shown that radiation-induced cardiac toxicity can be altered by PD-1 through cytotoxic T lymphocytes and suggest that PD-1 blockade should be administered with purposeful cardiac RT planning to ensure both positive treatment outcome and patient safety.…”

Acquired Immunity Is Not Essential for Radiation-Induced Heart Dysfunction but Exerts a Complex Impact on Injury

“…Du et al demonstrated with C57Bl/6 mice that whole-heart RT with PD-1 blockade led to increased mortality and cardiac dysfunction compared to mice that were only given cardiac RT [66]. With respect to the immune cell subtypes present, Myers and Lu saw increased mortality, as well as an increase in number of T cells, in the lungs and heart of C57Bl/6 mice that received thoracic RT and an anti-PD-1 antibody compared to mice given thoracic RT [67]. These findings suggest an enhanced sensitivity to cardiac RT when the immune system, specifically cytotoxic T lymphocytes, is no longer suppressed.…”

“…Recent advances in combinational cancer therapies, where the patient may receive radiation, as well as immunotherapy, hold great promise. In light of this, there is increasing interest in understanding how immunotherapy, including checkpoint inhibitors, could alter the effects of RT on the heart [66,67]. Radiation can alter immune responses, and the effects of radiation can change based on the state of both adaptive and innate immunity.…”

“…While there were studies to investigate the effects of combining cardiac RT and chemotherapeutic agents such as doxorubicin [68][69][70] and sunitinib [48], the cardiac effects of the combination of radiation and immunotherapies are less studied [66,67]. Because many immunotherapies target the mechanisms that restrain T cells to enhance tumor immunity, such as blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with ipilimumab [71] or programmed death protein 1 (PD-1) with pembrolizumab [72], these approaches could adversely impact normal cardiac tissue [66,67,71,72]. Du et al demonstrated with C57Bl/6 mice that whole-heart RT with PD-1 blockade led to increased mortality and cardiac dysfunction compared to mice that were only given cardiac RT [66].…”